1,4-diazacycloheptane derivatives

ABSTRACT

This invention provides substituted 1,2,3,4-tetrahydronaphthalene [ 3 H]-emopamil binding site inhibitors useful in the treatment of neurological disorders. Such inhibitors are compounds of formula (I)                    
     wherein R, R1, m, R2 and n are as defined in the specification. The invention also provides pharmaceutical compositions containing such compounds, methods of using such compounds and methods of making such compounds

This is a national stage application under 35 U.S.C. §317 ofPCT/GB98/03768, filed Dec. 15, 1998.

The present invention relates to chemical compounds, in particular1,4-diazacycloheptanes, to processes for their preparation and tochemical intermediates useful in such processes. The present inventionfurther relates to 1,4-diazacycloheptanes, to pharmaceuticalcompositions containing them and to their use in methods of therapeutictreatment of animals including man, in particular in the treatment ofneurological disorders.

Neurological disorders, for which the present compounds are useful,include stroke, head trauma, transient cerebral ischemic attack, andchronic neurodegenerative disorders such as Alzheimer's disease,Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis,multiple sclerosis, vascular dementia and AIDS-related dementia.

The compounds useful in the present invention are believed to act bybinding with the [³H]-emopamil binding site. Emopamil has classicallybeen thought of as a neuroprotective agent whose efficacy is most likelyderived from actions at either voltage-sensitive calcium channels (VSCC)or 5-HT₂ receptors. An apparent paradox to this logic is that verapamil,although chemically and pharmacologically very similar to emopamil, isnot neuroprotective. While the lack of neuroprotective efficacy byverapamil was initially explained by lack of CNS penetration, recentstudies suggest other factors may be involved (Keith et al., Br. J.Pharmacol. 113: 379-384, 1994).

[³H]-Emopamil binding defines a unique high affinity site that is notrelated to VSCC, is found in the brain, but is most prevalent in theliver (Moebius et al., Mol. Pharmacol. 43: 139-148, 1993). Moebius etal. have termed this the “anti-ischemic” binding site on the basis ofhigh affinity displacement by several chemically disparateneuroprotective agents. In liver, the [³H]-emopamil binding site islocalized to the endoplasmic reticulum.

Neuroprotective compounds are known, for example emopamil andifenprodil, that exhibit high affinity for the [³H]-emopamil bindingsite. However these are not selective inhibitors and exhibit activityeither at neuronal VSCC, the polyamine site of the NMDA receptor(N-Methyl-D-aspartate) and/or the sigma-1 binding site. We have nowfound a class of compounds that show selective action at the[³H]-emopamil binding site that are neuroprotective in global and focalmodels of cerebral ischemia without acting directly at either VSCC orNMDA receptors, and consequently exhibit fewer associated side effectsthan are conventionally seen with either emopamil (hypotension) orifenprodil (behavioural manifestations). Such compounds are especiallyuseful in treating neurodegeneration resulting from ischemia, forexample in Alzheimer's disease, vascular dementia, Parkinson's disease,Huntington's disease and AIDS-related dementia. In another aspect suchcompounds are especially useful in treating stroke as they provideneuronal protection by preventing neuronal death in the penumbra regionsurrounding the core infarct. Accordingly the present invention providesthe use of a compound which binds selectively to the [³H]-emopamilbinding site for treating neurodegeneration resulting from ischemia.

Accordingly the present invention provides a compound of the formula(I):

wherein:

R is hydrogen, C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₆alkyl,phenylC₁₋₆alkyl or phenyl;

R¹ is C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy, halo, hydroxy, C₁₋₆alkanoyl,haloC₁₋₆alkyl, cyano or nitro;

m is 0, 1 or 2;

R² is C₁₋₆alkyl;

n is 1, 1 or 2;

wherein any phenyl ring is optionally substituted; p1 or apharmaceutically acceptable salt or in vivo hydrolysable ester, amide orcarbanate thereof

Any phenyl ring in R may be optionally substituted, for example by up tofive substituents, preferably up to three substituents which may be thesame or different. Typical substituents include: hydroxy; C₁₋₆alkoxy forexample methoxy; mercapto; C₁₋₆alkylthio for example methylthio; amino;C₁₋₆alkylamino for example methylamino; di-(C₁₋₆alkyl)amino for exampledimethylamino; carboxy; carbamoyl; C₁₋₆alkylcarbamoyl for examplemethylcarbamoyl; di-C₁₋₆alkylcarbamoyl for example dimethylcarbamoyl;C₁₋₆alkylsulphonyl for example methylsulphonyl; arylsulphonyl forexample phenylsulphonyl; C₁₋₆alkylaminosulphonyl for examplemethylaminosulphonyl; di-(C₁₋₆alkyl)aminosulphonyl for exampledimethylamino-sulphonyl; nitro; cyano; cyano-C₁₋₆alkyl for examplecyanomethyl; hydroxyC₁₋₆alkyl for example hydroxymethyl; amino-C₁₋₆alkylfor example aminoethyl; C₁₋₆alkanoyl-amino for example acetamido;C₁₋₆alkoxycarbonylamino for example methoxycarbonylamino; C₁₋₆alkanoylfor example acetyl; C₁₋₆alkanoyloxy for example acetoxy; C₁₋₆alkyl forexample methyl, ethyl, isopropyl or tert-butyl; halo for example fluoro,chloro or bromo; trifluoromethyl or trifluoromethoxy. In another aspecta further typical substituent for any phenyl group is phenylC₁₋₆alkoxy.

In one aspect the present invention provides a compound of the formula(I) or a pharmaceutically acceptable salt or in vivo hydrolysable amideor carbamate thereof, wherein

R is hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₆alkyl,phenylC₁₋₆alkyl or phenyl;

R¹ is

C₁₋₆alkyl, C₁₋₆alkoxy, halo, hydroxy, haloC₁₋₆alkyl, cyano or nitro; mis 0, 1 or 2; R² C₁₋₆alkyl; and n is 0, 1 or 2; wherein any phenyl ringis optionally substituted.

Suitably R is hydrogen; C₁₋₁₀alkyl for example methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, pentyl (n-pentyl or 3-methylbutyl) or2-ethylheptyl; C₃₋₈cycloalkyl for example cyclopropyl, cyclobutyl orcyclopentyl; C₃₋₈cycloalkylC₁₋₆alkyl for example cyclopropylmethyl,cyclobutylmethyl or cyclopentylmethyl; phenylC₁₋₆alkyl for examplebenzyl, 2-phenethyl or 3-phenylpropyl.

Favourably R is hydrogen or C₁₋₆alkyl. In particular R is hydrogen orC₁₋₄alkyl such as methyl, ethyl, isopropyl, n-propyl, n-butyl orisobutyl. In particular also R is C₅₋₆alkyl for example 3-methylbutyl.Another particular value for R is phenylC₁₋₆alkyl for example benzyl,2-phenethyl or 3-phenylpropyl. In one aspect R is C₁₋₆alkyl orphenylC₁₋₆alkyl. Preferably R is methyl, 3-methylbutyl or3-phenylpropyl. In one aspect R is C₁₋₆alkyl or phenylC₁₋₆alkyl.

Suitably R¹ is C₁₋₆alkyl for example methyl, ethyl or propyl;C₂₋₆alkenyl for example vinyl; C₁₋₆alkoxy for example methoxy, ethoxy orpropoxy; halo for example bromo, chloro or fluoro; hydroxy; C₁₋₆alkanoylfor example formyl or acetyl; haloC₁₋₆alkyl for example trifluoromethyl;cyano or nitro

In one aspect R¹ is C₁₋₆alkyl, C₁₋₆alkoxy, halo, hydroxy, haloC₁₋₆alkyl,cyano or nitro.

Preferably R¹ is C₁₋₆alkoxy for example methoxy or ethoxy or is halo forexample bromo chloro or fluoro. In a particularly preferred aspect, m isone and R¹ is methoxy, for example at the 5-position or the 7-positionof the 1,2,3,4-tetrahydronaphthalene ring system, most preferably at the5-position. In another particularly preferred aspect, m is one and R¹ isbromo or fluoro, for example at the 6-position of the1,2,3,4-tetrahydronaphthalene ring system.

In another preferred aspect m is zero.

Suitably R² is C₁₋₆alkyl for example methyl or ethyl.

In a preferred aspect n is zero.

A particular class of preferred compounds is that of the formula (II):

wherein R³ is hydrogen, or C₁₋₆alkyl or pheny C₁₋₆alkyl and R⁴ ishydrogen or C₁₋₆alkoxy. In one aspect R³ is C₁₋₆alkyl. In particular inthe compounds of the formula (II), R⁴ is hydrogen and R³ is methyl,3-methylbutyl or 3-phenylpropyl.

Particular compounds of the present invention include those of theExamples hereinafter;4-(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine1-methyl-4-(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazineand1-isopropyl-4-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

The compounds of the present invention possess a chiral centre at the1-position of the 1,2,3,4-tetrahydronaphthalene ring system (that is thecarbon atom to which the nitrogen containing ring is attached). Otherchiral centres may be present when n is one or two and in any of thesubstituents R-R⁴.

The present invention covers all enantiomers, diastereoisomers andmixtures thereof of the compound of the formula (I) that inhibit the[3H]-emopamil binding site.

As mentioned hereinabove, the compounds of the present invention possessa chiral centre at the 1-position of the 1,2,3,4-tetrahydronaphthalenering system. It is preferred that this centre has the S-stereochemistryunder the Cahn-Prelog-Ingold sequence rules. It is preferred that any Ror S-enantiomer is substantially free of the corresponding S orR-enantiomer, suitably 90%, more suitably 95%, and for example 96%, 97%,98% or 99% free of the other enantiomer.

Suitable pharmaceutically acceptable salts include acid addition saltssuch as hydrochloride, hydrobromide, citrate and maleate salts and saltsformed with phosphoric and sulphuric acid. In another aspect suitablesalts are base salts such as an alkali metal salt for example sodium orpotassium, an alkaline earth metal salt for example calcium ormagnesium, or organic amine salt for example triethylamine.

In vivo hydrolysable esters, amides and carbamates hydrolyse in thehuman body to produce the parent compound. Such esters, amides andcarbamates can be identified by administering, for example intravenouslyto a test animal, the compound under test and subsequently examining thetest animal's body fluids. Suitable in vivo hydrolysable groups includeN-carbomethoxy and N-acetyl.

In order to use a compound of the formula (I) or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester amide or carbamate thereoffor the therapeutic treatment (including prophylactic treatment) ofmammals including humans, it is normally formulated in accordance withstandard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula (I)or a pharmaceutically acceptable salt or an in vivo hydrolysable esteramide or carbamate and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by oral, topical, parenteral, buccal, nasal, vaginal orrectal administration or by inhalation. For these purposes the compoundsof this invention may be formulated by means known in the art into theform of, for example, tablets, capsules, aqueous or oily solutions,suspensions, emulsions, creams, ointments, gels, nasal sprays,suppositories, finely divided powders or aerosols for inhalation, andfor parenteral use (including intravenous, intramuscular or infusion)sterile aqueous or oily solutions or suspensions or sterile emulsions. Apreferred route of administration is intravenously in sterile isotonicsolution.

In addition to the compounds of the present invention the pharmaceuticalcomposition of this invention may also contain, or be co-administered(simultaneously or sequentially) with, one or more pharmacologicalagents of value in treating one or more disease conditions referred tohereinabove.

The pharmaceutical compositions of this invention will normally beadministered to humans so that, for example, a daily dose of 0.05 to 75mg/kg body weight (and preferably of 0.1 to 30 mg/kg body weight) isreceived. This daily dose may be given in divided doses as necessary,the precise amount of the compound received and the route ofadministration depending on the weight, age and sex of the patient beingtreated and on the particular disease condition being treated accordingto principles known in the art.

Typically unit dosage forms will contain about 1 mg to 500 mg of acompound of this invention.

Therefore in a further aspect, the present invention provides a compoundof the formula (I) or a pharmaceutically acceptable salt or an in vivohydrolysable ester, amide or carbamate thereof for use in a method oftherapeutic treatment of the human or animal body.

In yet a further aspect the present invention provides a method oftreating a disease condition wherein inhibition of the [³H]-emopamilbinding site is beneficial which comprises administering to awarm-blooded animal an effective amount of a compound of the formula (I)or a pharmaceutically acceptable salt or an in vivo hydrolysable ester,amide or carbamate thereof. The present invention also provides the useof a compound of the formula (I) or a pharmaceutically acceptable saltor an in vivo hydrolysable ester, amide or carbamate thereof in thepreparation of a medicament for use in a disease condition.

In another aspect the present invention provides a process for preparinga compound of the formula (I) or a pharmaceutically acceptable salt oran in vivo hydrolysable ester, amide or carbamate thereof which processcomprises:

a) reacting a compound of the formula (III) with a compound of theformula (IV):

wherein R, R¹, R², m and n are as hereinbefore defined and L is aleaving group; or

b) deprotecting a compound of the formula (V):

wherein R¹, R², m and n are as hereinbefore defined and P is aprotecting group for R;

wherein any functional group is protected, if necessary, and:

i) removing any protecting groups;

ii) optionally converting a compound of the formula (I) into anothercompound of the formula (I);

iii) optionally forming a pharmaceutically acceptable salt or an in vivohydrolysable ester, amide or carbamate.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled; chemist asappropriate for the protection of the group in question, and may beintroduced by conventional methods.

Protecting groups may be removed by any convenient method as describedin the literature or known to the skilled chemist as appropriate for theremoval of the protecting group in question such methods being chosen soas to effect removal of the protecting group with minimum disturbance ofgroups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower” signifies that the group to which it isapplied preferably has 1-4 carbon atoms. It will be understood thatthese examples are not exhaustive. Where specific examples of methodsfor the removal of protecting groups are given below these are similarlynot exhaustive. The use of protecting groups and methods of deprotectionnot specifically mentioned is of course within the scope of theinvention.

A carboxyl protecting group may be the residue of an ester-formingaliphatic or araliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).

Examples of carboxy protecting groups include straight or branched chain(1-12C)alkyl groups (eg isopropyl, t-butyl); lower alkoxy lower alkylgroups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl); loweraliphatic acyloxy lower alkyl groups, (eg acetoxymethyl,propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); loweralkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl,1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg benzyl,p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl andphthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl andt-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (egtrimethylsilylethyl); and (2-6C)alkenyl groups (eg allyl andvinylethyl).

Methods particularly appropriate for the removal of carboxyl protectinggroups include for example acid-, base-, metal- or enzymically-catalysedhydrolysis.

Examples of hydroxyl protecting groups include lower alkyl groups (egt-butyl), lower alkenyl groups (eg allyl); lower alkanoyl groups (egacetyl); lower alkoxycarbonyl groups (eg t-butoxycarbonyl); loweralkenyloxycarbonyl groups (eg allyloxycarbonyl); aryl loweralkoxycarbonyl groups (eg benzoyloxycarbonyl,p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (eg trimethylsilyl,t-butyldimethylsilyl) and aryl lower alkyl (eg benzyl) groups.

Examples of amino protecting groups include formyl, aralkyl groups (egbenzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyyl andfurylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl); loweralkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonylgroups (eg benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); trialkylsilyl (egtrimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene);benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis, for groups such as p-nitrobenzyloxycarbonyl, hydrogenationand for groups such as o-nitrobenzyloxycarbonyl, photolytically.

Pharmaceutically acceptable salts of the compound of the formula (I) maybe prepared in any conventional manner for example from the free baseand acid. In vivo hydrolysable esters, amides and carbamates may beprepared in any conventional manner.

The reaction between the compounds of the formulae (III) and (IV) isperformed in conventional manner. Typically this reaction takes place inorganic solvent for example an anhydrous aprotic solvent such asdimethylformamide, dimethylacetamide or tetrahydrofuran. The reaction isgenerally performed in the presence of a catalyst, such as an iodidesalt for example potassium iodide, and is generally performed atambient. or elevated temperature for example 0°-100° C., more preferably40°-80° C.

In the compounds of the formula (III), L is a conventional leaving groupsuch as halo for example chloro, iodo or bromo; or a tosylate forexample p-toluenesulphonyloxy or methanesulphonyloxy.

In the compounds of the formula (III), the leaving group L may alsorepresent oxo (═O), forming an a-tetralone ring system. Such compoundsmay be reacted with a compound of the formula (IV) under conventionalconditions for reductive amination. Suitable conditions include thepresence of a reducing agent such as hydrogen and a hydrogenationcatalyst (for example palladium on carbon), or zinc and hydrochloricacid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, orsodium borohydride, iron pentacarbonyl and alcoholic potassiumhydroxide, or borane and pyridine or formic acid. The reaction ispreferably carried out in the presence of a suitable solvent such as analcohol, for example methanol or ethanol, and at a temperature in therange of 0-50° C., preferably at or near room temperature.

The compounds of the formula (III) are either known or may be preparedin conventional manner as known to the organic chemist skilled in theart. One convenient manner is to convert the corresponding1-hydroxy-1,2,3,4-tetrahydronaphthalene to the compound of the formula(III); for example by treating with thionyl chloride in the presence ofpyridine to prepare the compound of the formula (III) wherein L ischloro.

Compounds of the formula (V) wherein P is a protecting group convertibleto R may be deprotected in standard manner. Any suitable N-protectinggroup may be used and deprotected in conventional manner. Favourably Pis C₁₋₆alkoxycarbonyl and such compounds may be converted to compoundsof the formula (I) wherein R is methyl for example by treating with areducing agent such as lithium aluminium hydride. Certain compounds ofthe formula (V) are also in vivo hydrolysable esters, amides orcarbamates of the compounds of the formula (I).

Compounds of the formula (I) wherein R is hydrogen may be converted tocompounds of the formula (I) wherein R is other than hydrogen. Forexample such conversion may comprise conventional methods of alkylationwith an appropriate alkylating agent or reductive amination. For examplean isopropyl group may be prepared by reacting a compound of the formula(I) wherein R is hydrogen with acetone in the presence of a reducingagent such as sodium borohydride or sodium cyanoborohydride. A2-methylpropyl group may be prepared by reacting a compound of theformula (I) wherein R is hydrogen with isobutyric acid in the presenceof a reducing agent such as sodium borohydride or sodiumcyanoborohydride.

Thus in another aspect the present invention provides a process forpreparing a compound of the formula (I) wherein R is not hydrogen,especially where R is C₁₋₁₀alkyl, from a compound of the formula (I)wherein R is hydrogen by reaction with an alkylating agent or byreductive amination.

As mentioned hereinabove, the compounds of the present invention possessa chiral centre at the 1-position of the 1,2,3,4-tetrahydronaphthalenering system and the present invention encompasses the racemate andindividual enantiomers. Enantiomers of the compound of the formula (I)may be prepared in conventional manner by resolution of a racemiccompound. Alternatively enantiomers of the compounds of the formula (I)may be prepared in analogous manner to the racemates commencing withchiral starting-materials. In yet a further alternative, a chemicalintermediate, for example of the formula (III), or the correspondinghydroxy compound, or of the formula (V), may be resolved andsubsequently reacted without destroying chirality.

The following biological test methods, data and Examples serve toillustrate the present invention.

³H-Emopamil Binding to Guinea Pig Liver Membranes

The method of (−)-³H-emopamil binding was a modification of Zech, C.,Staudinger R., Mühlbacher, J. and Glossmann, H. Novel sites forphenylalkylamines: characterization of a sodium-sensitive drug receptorwith (−)-³H-emopamil. Eur. J. Pharm. 208: 119-130, 1991.

The reaction mixture contained:

Assay buffer: 10 mM Tris-HCl, 0.1 mM phenylmethylsulfonyl fluoride(PMSF), 0.2% bovine serum albumin (BSA), pH 7.4 at 4° C.

Radioligand: 0.96 nM (−)-³H-emopamil (Amersham).

Guinea pig liver membranes: 40 mg/mL original wet weight.

Compounds: 1-300 nM.

Total volume: 500 μL.

This mixture was incubated for 60 minutes at 37° C. The incubation wasterminated by filtering with a Brandel Cell Harvester over Whatman GF/Cfilters that had been soaked for at least 120 minutes in 0.3%polyethylenimine (PEI) and washed three times with 5 mL of wash buffercontaining 10 mM Tris-HCl, 10 mM MgCl₂, 0.2% BSA, pH 7.4 at 25° C.Specific binding was defined with 10 μM emopamil. In general compoundswith an IC₅₀ Specific binding was defined with 10 μM emopamil. Ingeneral compounds with an IC₅₀ below 300 nM in this test were ofinterest and for example the compound of Example 4 gave a value of 17nM.

Guinea-pig liver membrane preparation: Male guinea pigs were sacrificedby CO₂ asphyxiation with dry ice. The livers were quickly excised andweighed and rinsed in membrane preparation buffer containing 10 mMHepes, 1 mM Tris base-EDTA, 250 mM driven Teflon-glass homogenizer withthree strokes on ice. The homogenate was centrifuged driven Teflon-glasshomogenizer with three strokes on ice. The homogenate was centrifuged at1000×g in a SS34 rotor for 5 minutes at 4° C. The supernatant wasfiltered through 4 layers of gauze and then centrifuged at 8000×g for 10minutes at 4° C. This resulting supernatant was centrifuged at 40,000×gfor 15 minutes at 4° C. The resulting pellet was resuspended in assaybuffer and centrifuged again at 40,000×g for 15 minutes at 4° C. Thispellet was resuspended in assay buffer (2.5 fold with respect tooriginal wet weight) and homogenized with one stroke with theTeflon-glass homogenizer. Aliquots of 1 mL were stored at −70° C.

³H-D-888 Binding to Rat Brain Cortical Membranes

The method of ³H-D-888 binding was a modification of Reynolds, I. J.,Snowman, A. M. and Synder, S. H. (−)-[³H] Desmethoxyverapamil labelsmultiple calcium channel modular receptors in brain and skeletal musclemembranes: differentiation by temperature and dihydropyridines. J.Pharmacol. Exp. Ther. 237: no.3, 731-738, 1986.

The assay tubes contained the following:

assay buffer: 50 mM Hepes, 0.2% BSA, pH 7.4

radioligand: 1 πM ³H-D888 (Amersham)

rat cortical membranes: 6 mg/ml original wet weight

compounds: 0.3-100 μM

Total volume: 1000 μL

This mixture was incubated for 60 minutes at 25° C. The assay wasterminated by filtering with a Brandel Cell Harvester over Whatman GF/Cfilters that had been soaked for at least 120 minutes in 0.3%polyethylenamine (PEI) and washed three times with 5 mL of wash buffercontaining 20 mM Hepes, 20 mM MgCl₂, pH 7.4. Specific binding wasmeasured with 10 μM methoxyverapamil (D-600). This assay was used todetermine in vitro selectivity of compounds vs. L-type voltage sensitivecalcium channels, i.e high affinity for the ³H-D888 binding site wouldshow a lack of selectivity. For example the compound of Example 4 gave avalue of about 19.000 nM in this test.

Rat brain cortical membrane preparation: Male Sprague-Dawley Rats weresacrificed by decapitation and the brains were quickly excised. Thecerebellum and brain stem were removed and discarded; and the rest ofthe brain was rinsed in 320 mM sucrose. The brain was then homogenizedin a 10-fold volume of 320mM sucrose with a motor driven Teflon-glasshomogenizer using 10 strokes on ice. The homogenate was spun at 1000×gfor 10 glass homogenizer using 10 strokes on ice. The homogenate wasspun at 1000×g for 10 minutes at 4° C. in a SS-34 rotor. The supernatantwas then spun at 29,000×g for 20 minutes. The resulting pellet wasresuspended in membrane buffer (5 mM Hepes, 0.2% BSA, pH 7.4 ) to afinal concentration of 60 mg original wet weight/mL.

Gerbil Global Model of Cerebral Ischemia

Male Mongolian gerbils (Charles River) weighing 60-70 grams are used inthese experiments. They are housed in individual cages with food (PurinaRodent Chow) and water available ad libitum. The animal room ismaintained at 23° C.±2°, and is on an automatic 12 hour light cycle.

The gerbils are brought to the surgical suite and dosedintraperitoneally with the test agent or vehicle, forty five minutesprior to surgery. Drugs are administered at a volume of 5 ml/kg(intraperitoneal). Vehicle is generally saline, with sodium phosphateadded to adjust pH, if needed. Forty-five minutes after dosing thegerbils are anesthetized with halothane (3.3%) which is delivered alongwith oxygen (1.5 L/M) through a face mask. After the gerbils areanesthetized, halothane is continued at a maintenance level of 1.5-2%along with oxygen. The ventral surface of the neck is shaved and cleanedwith alcohol. Surgical procedures are carried out on athermostat-controlled heating pad set to 37° C. An incision is made inthe neck, the carotid arteries are dissected away from the surroundingtissue, and isolated with a 5 cm length of Silastic tubing. When botharteries have been isolated they are clamped with microaneurysm clips(Roboz Instruments). The arteries are visually inspected to determinethat the blood flow has been stopped. After 5 minutes the clips aregently removed from the arteries and blood flow begins again. A shamcontrol group is treated identically but is not subjected to carotidartery occlusion. The incisions are closed with suture and the gerbilsremoved from the anesthesia masks and placed on another heating pad torecover from the anesthesia. When they have regained the righting reflexand are beginning to walk around, they are again dosed with the testcompound and returned to their home cages. This occurs approximatelyfive minutes after the end of surgery.

Twenty-four hours post ischemia gerbils are tested for spontaneouslocomotor activity, using a Photobeam Activity System from San DiegoInstruments. They are individually placed in Plexiglas chambersmeasuring 27.5 cm×27.5 cm×15 cm deep. The chambers are surrounded byphotocells, and every time a beam is broken one count is recorded. Eachgerbil is tested for two hours, and cumulative counts are recorded at30, 60, 90, and 120 minutes. Mean counts are recorded for each group anddrug groups are compared to control with an ANOVA and Bonferroni posttest. After each gerbil is tested it is returned to its home cage. Atthis time gerbils are also observed for any changes from normalbehavior.

For the next two days no specific testing is performed, but the gerbilsare observed two to three times per day for any unusual behaviors orobvious neurological symptoms (i.e. ataxia, convulsions, stereotypicbehavior). Four days post ischemia the gerbils are sacrificed bydecapitation and their brains removed and preserved in 10% bufferedformalin. Brains were removed, fixed and stained with hematoxylin andeosin. Under a light microscope, hippocampal fields were observed andgraded for damage to the CA1 subfield: 0 to 4 scale, with 0 representingno damage and 4 representing extensive damage.

Transient Focal Ischemia in Rats

The method was as described by Lin, T-N., He, Y. Y., Wu, G., Khan, M.And Hsu, C. Y. Effect of brain edema on infarct volume in a focal modelcerebral ischemia model in rats. Stroke 24:117-121, 1993, which model isconsidered to be relevant to the clinical situation. Male Long-Evansrats 250-350 g were used. Surgery leading to focal ischemia wasconducted under anesthesia with 100 mg/kg ketamine and 5 mg/kg i.m.xylazine. Rectal temperature was monitored and maintained at 37.0±0.5deg C. The right middle cerebral artery (MCA) was exposed usingmicrosurgical techniques. The MCA trunk was ligated immediately abovethe rhinal fissure with 10-0 suture. Complete interruption of blood flowwas confirmed under an operating microscope. Both common carotidarteries were then occluded using nontraumatic aneurysm clips. After apredetermined duration of ischemia (45 min), blood flow was restored inall three arteries. Twenty-four hours post occlusion, rats were killedunder ketamine anesthesia by intracardiac perfusion with 200 ml of 0.9%NaCl. The brain was removed and processed with 2% triphenyltetrazoliumchloride to identify and quantitate the infarcted brain region.Compounds were administered by intravenous infusion for 4 hours.

In the examples:

a) all nmr spectra were recorded at 300 MHz and were recorded in CDCl₃unless otherwise stated;

b) evaporation of solvents was carried out under reduced pressure;

c) DMF means N,N-dimethylformamide;

d) DMAC means N,N-dimethylacetamide;

e) THF means tetrahydrofuran.

EXAMPLE 1 1-Methyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A 1 liter 3-necked flask equipped with a condenser, electronicthermocouple, mechanical stirrer and under a nitrogen atmosphere wascharged with a solution of N-methylhomopiperazine (60 ml; 0.476 mol) inDMF (200 ml). Potassium iodide (8.7 g) was added followed by theaddition in one portion of a solution of1,2,3,4-tetrahydro-1-chloronaphthalene (36.8 g: 0.22 mol) in DMF (150ml). This solution was then heated at 68° C. for 18 hours and thesolvent was removed in vacuo using a rotary evaporator. The resultingconcentrate was diluted with water (800 ml) and extracted with ethylacetate (3×300 ml) which was washed with brine and dried with sodiumsulphate. Filtration and evaporation of solvent gave a brown oil (47.3g) which was purified by flash chromatography using 2000 ml of silicagel and eluting with methylene chloride:methanol:ammonium hydroxide ingradients of 94:5:1, 89:10:1 and 79:20:1. The resulting tan oil (46.5 g)was distilled using a Kugelrohr to give the title compound as a yellowoil (38.8 g); bp (air bath temperature) 123-138° C. at 650-950 mtorr; ¹Hnmr δ 3.86-3.91(m, 1H), 7.03-7.78 (m, 3H), 7.76-7.78 (d, 1H).

A solution of the above base (38.8 g) in ethanol (800 ml) was treatedwith saturated ethanolic HCl (400 ml). While stirring, diethyl ether(1200 ml) was added over 10 minutes, resulting in the separation of awhite solid after 15 minutes. After 2 hours this solid was collected byfiltration and dried at 70° C. in vacuo to yield the dihydrochloride ofthe title compound (44.6 g) mp 221-222° C. Anal; Calcd. for C₁₆H₂₄N₂.2HCl.0.3 H2O: C, 59.55; H, 8.31; N, 8.68. Found: C, 59.40; H, 8.28; N.8.40.

A solution of the base (1.46 g) in ethanol (31 ml) was treated with anethereal solution (62 ml) saturated with maleic acid (prepared bydissolving 1.94 gm of maleic acid in 70 ml of diethyl ether) and left atambient temperature overnight. The resulting white solid was collectedby filtration and dried in vacuo at 57° C. to give the dimaleate salt ofthe title compound (2.61 g) mp 125.4-126.3° C. Anal; Calcd. forC₁₆H₂₄N₂.2C₄H₄O₄: C, 60.49; H, 6.77; N, 5.88. Found: C, 60.48; H, 6.64;N, 5.96. 1,2,3,4-Tetrahydro-1-chloronaphthalene was prepared as follows:

A 1 liter 3-necked flask equipped with a condenser, electronicthermocouple, mechanical stirrer and under a nitrogen atmosphere wascharged with 1,2,3,4-tetrahydro-1-naphthol (34.3 g; 0.23 mol) in drydiethyl ether (420 ml). Pyridine (4.7 ml) was added and the flask wascooled to 16° C. in a bath of water and ice. A solution of thionylchloride (50.7 ml; 0.70 mol) in ether (140 ml) was then added dropwisein 25 minutes and stirring continued overnight while allowing the bathto warm to ambient temperature. The reaction mixture was then pouredinto cold brine (400 g ice and 800 ml brine) and the organic phase wasseparated. The aqueous phase was extracted with diethyl ether (2×150 ml)and the combined organic extract was dried with sodium sulphate.Filtration and removal of solvent in vacuo gave1,2,3,4-tetrahydro-1-chloronaphthalene (36.9 g) as an oil. This materialwas used without further purification.

EXAMPLE 2 N-(1,2,3,4-Tetrahydro-1-naphthalenyl)homopiperazine

A 250 ml 3-necked flask equipped with a condenser and magnetic stirringbar and under a nitrogen atmosphere was charged with a solution ofhomopiperazine (19.2 g; 186 mmol) in DMF (90 ml). Potassium iodide (100mg) was added followed by the addition by pipette of a solution of1,2,3,4-tetrahydro-1-chloronaphthalene (6.35 g; 38.1 mmol) in DMF (20ml). This solution was then heated in an oil bath at 55° C. for 43hours. The reaction mixture was partitioned between water and ethylacetate, washed with brine and dried with magnesium sulphate. Filtrationand evaporation of solvent gave an amber liquid (7.5 g) which waspurified by Kugelrohr distillation to give the title compound as a paleyellow oil (5.3 g) bp (air bath temperature) 120-140° C. at 90 mtorr;tlc analysis on silica gel (CH₂Cl₂:CH₃OH:NH₄OH, 89:10:1) showed a singlecomponent, R_(f) 0.11; ¹H nmr δ 3.90-3.95 (m, 1H, benzylic CHN),7.03-7.37 (m, 3H), 7.77-7.80 (d, 1H).

An ethanolic solution (21 ml) containing this base (1.00 g) was treateddropwise with an ethereal solution (43 ml) saturated with maleic acid tothe cloud point. A gum which formed on standing very slowly solidified.This white solid was collected by filtration, washed with ether anddried at 60° C. at high vacuum to yield the salt of the title compound(0.95 g) mp 107-109.4° C.; ¹H nmr (300 MHz, d₆-DMSO) δ 3.96 (m, 1H,benzylic CHN), 6.11 (3.44H, CH═CH, maleic acid), 7.05-7.18 (m, 3H), 7.72(d, 1H). Anal. Calcd. for C₁₅H₂₂N₂.1.70C₄H₄O₄: C, 61.22; H, 6.79; N,6.55. Found: C, 61.06; H, 6.91; N, 6.73.

EXAMPLE 3 S(+) N-(1,2,3,4-Tetrahydro-1-naphthalenyl)homopiperazine

S(+) N-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine was obtained asthe first material to elute on subjecting racemic material (5.3 g),prepared as in Example 2, to preparative Chiral Pak AD HPLC resolutionusing a hexane/ethanol mixture with modification with diethylamine. Theenantiomeric purity was determined on an analytical scale usinghexane:ethanol:diethylamine (90:5:.05, v/v) and detection at 220 nm. Thesolution containing this enantiomer was concentrated using a rotaryevaporator to give the title compound (2.35 g), [α]_(D) ²²+108° (c=0.50,methanol); 98% ee.

To a solution of this base (1.0 g; 4.35 mmol), in ethanol (25 ml) wasadded by pipette a solution of maleic acid (1.1 g; 9.47 mmol) in ether(40 ml). Addition of ether (5 ml) resulted in a cloudiness and, onstanding, the formation of a white precipitate. This solid was collectedby filtration and dried in a drying pistol (50° C., 70 mtorr) to yieldthe dimaleate of the title compound (0.76 g), mp 106-107.5° C.; [α]_(D)²²+44.7° (c=0.38, methanol). Anal: Calcd. for C₁₅H₂₂N₂.2C₄H₄O₄: C,59.73; H, 6.53; N, 6.05. Found: C, 59.83; H, 6.62; N, 6.00.

EXAMPLE 4 S(+)1-Methyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A dry 100 ml 3-necked flask equipped with a condenser, addition funneland magnetic stirring bar was charged with lithium aluminum hydride(0.36 g; 9.48 mmol) and dry THF (10 ml) under a nitrogen atmosphere.S(+) N-Carbethoxy-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine(1.35 g: 4.47 mmol) in THF (10 ml) was added dropwise and the solutionwas heated to reflux for 3 hours and cooled to ambient temperature.Saturated sodium sulphate (10 ml) was added dropwise at a rate amenableto maintaining control of the reaction and the content of the flask wasfiltered through diatomaceous earth and dried (MgSO₄). Filtration andremoval of solvent in vacuo gave a yellow oil (1.06 g) which waskugelrohr distilled to give the title compound (0.97 g) bp (air bathtemperature) 150° C. at 100 mtorr., homogeneous by tlc (silica gel,CH₃OH:CH₂Cl₂:NH₄OH 10:89:1), R_(f) 0.40; ¹H-nmr δ 3.88-3.91 (m, 1H,benzylic CHN), 6.97-7.25 (m, 3H), 7.75-7.78 (d, 1H); [α]_(D) ²²+85.2°(c=0.54, methanol).

To a solution of the base (0.91 g) in ethanol (25 ml) was added bypipette a solution of maleic acid (1.0 g) in ether (40 ml). Uponcompletion of the addition, a white precipitate formed. This solid wascollected by filtration and was dried overnight in a drying pistol (50°C. at 100 mtorr) to yield the dimaleate salt of the title compound (1.40g) mp 135.1-135.3; ¹H-nmr (300 MHz, d₆-DMSO) δ 3.95-3.98 (m, 1H,benzylic, CHN), 6.11 (s, CH═CH, maleic acid), 7.05=7.71 (m, 3H),7.69-7.71 (d, 1H): [α]_(D) ²²+41° (c=0.245, methanol). Anal: Calcd. forC₁₆H₂₄N₂.2C₄H₄O₄: C, 6049; H, 6.77; N, 5.88. Found: C, 60.20; H, 6.74;N, 5.99.

S(+) N-Carbethoxy-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazinewas obtained as follows:

A dry 50 ml 3-necked flask equipped with a condenser, addition funneland magnetic stirring bar under a nitrogen atmosphere was charged withS(+) N-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine (1.0 g; 4.34mmol) and methylene chloride (15 ml). Triethylamine (0.80 ml; 5.74 mmol)was added and the flask was cooled in a Dry Ice/acetone bath. Ethylchloroformate (0.50 ml; 5.23 mmol), in methylene chloride (10 ml) wasadded dropwise and the mixture was allowed to warm to ambienttemperature slowly. After stirring overnight, the content of the flaskwas partitioned between water and methylene chloride, the organic phasewas washed with brine and the solution was dried with magnesiumsulphate. Filtration and removal of solvent gave an amber oil (1.30 g),homogeneous by tlc (silica gel, ethyl acetate), R_(f) 0.68; ¹H-nmr δ1.24-1.28 (t, 3H), 4.11-4.18 (q, 2H), 7.03-7.26 (m, 3H), 7.74(1H).

EXAMPLE 5 R(−) N-(1,2,3,4-Tetrahydro-1-naphthalenyl)homopiperazine

R(−) N-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine was obtained asthe second material to elute on subjecting racemic material (5.3 g),prepared as in Example 2, to preparative Chiral Pak AD HPLC resolutionusing a hexane/ethanol mixture with modification with diethylamine. Theenantiomeric purity was determined on an analytical scale usinghexane:ethanol:diethylamine (90:5:.05, v/v) and detection at 220 nm. Thesolution containing this enantiomer was concentrated using a rotaryevaporator to give the title compound (2.65 g), [α]_(D) ²²−94° (c=0.64,methanol); 98.5% ee.

To a solution of this base (1.1 g: 4.78 mmol) in ethanol (25 ml) wasadded by pipette a solution of maleic acid (1.2 g; 10.33 mmol) in ether(40 ml) and the formation of a white solid was promoted by scratching.This solid was collected by filtration and dried in a drying pistol (50°C., 70 mtorr) to yield the dimaleate salt of the title compound (1.2 g),mp 108-110° C.; [α]_(D) ²²−41.6° (c=0.60, methanol). Anal. Calcd. forC₁₅H₂₂N₂.2C₄H₄O₄: N, 6.05. Found: C, 59.62; H, 6.56; N, 6.09.

EXAMPLE 6 R(−)1-Methyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A dry 50 ml 3-necked flask equipped with a condenser, addition funneland magnetic stirring bar was charged with lithium aluminum hydride(0.37 g, 9.75 mmol) and dry THF (10 ml) under a nitrogen atmosphere.R(−) N-Carbethoxy-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine(1.45 g; 4.80 mmol) in THF (10 ml) was added dropwise and the solutionwas heated to reflux for 3 hours and cooled to ambient temperature.Saturated sodium sulphate (10 ml) was added dropwise at a rate amenableto maintaining control of the reaction and the content of the flask wasfiltered through diatomaceous earth and dried (MgSO₄). Filtration andremoval of solvent in vacuo gave a yellow oil (1.06 g) which waskugelrohr distilled to give the title compound (0.97 g), bp (air bathtemperature) 120-130° C. at 70 mtorr., homogeneous by tlc (silica gel,CH₃OH:CH₂Cl₂:NH₄OH 10:89:1), R_(f) 0.40; ¹H-nmr δ 3.87-3.91 (m, 1H,benzylic CHN), 6.98-7.26 (m, 3H), 7.76-7.78 (d, 1H); [α]_(D) ²²−86.5°(c=0.70, methanol).

To a solution of the base (0.95 g) in ethanol (25 ml) was added bypipette a solution of maleic acid (1.0 g) in ether (40 ml). Uponcompletion of the addition, a white precipitate formed. This solid wascollected by filtration and was dried overnight in a drying pistol (50°C. at 100 mtorr) to yield the dimaleate salt of the title compound (1.59g), mp 138-139; ¹H-nmr (300 MHz, d₆-DMSO) δ 3.95-3.98 (m, 1H, benzylic,CHN), 6.11 (s, CH═CH, maleic acid), 7.05=7.71 (m, 3H), 7.69-7.71 (d,1H). Anal: Calcd. for C₁₆H₂₄N₂.2C₄H₄O₄: C, 60.49; H, 6.77; N, 5.88.Found: C, 60.60; H, 6.65; N, 6.08.

R(−) N-Carbethoxy-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazinewas obtained as follows:

A dry 100 ml 3-necked flask equipped with a condenser, addition funneland magnetic stirring bar under a nitrogen atmosphere was charged withof R(−) N-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine (1.1 g; 4.78mmol) and methylene chloride(19 ml). Triethylamine (0.80 ml; 5.74 mmol)was added and the flask was cooled in a Dry Ice/acetone bath. Ethylchloroformate (0.50 ml; 5.23 mmol) in methylene chloride (9 ml) wasadded dropwise and the mixture was allowed to warm to ambienttemperature slowly. After stirring overnight the content of the flaskwas partitioned between water and methylene chloride, the organic phasewas washed with brine and the solution was dried with magnesiumsulphate. Filtration and removal of solvent gave an yellow oil (1.50 g),homogeneous by tlc (silica gel, ethyl acetate); ¹H-nmr δ 1.24-1.28 (t,3H), 4.11-4.18 (q, 2H), 7.03-7.26 (m, 3H), 7.71-7.73 (d, 1H).

EXAMPLE 71-Methyl-4-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A 50 ml 3-necked flask equipped with a condenser, addition funnel,mechanical stirrer and under a nitrogen atmosphere was charged with asolution of N-methylhomopiperazine (5.40 g; 47 mmol) in DMF (31 ml).Potassium iodide (8.86 g) was added followed by the addition of asolution of 1-chloro-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.63 g;23.5 mmol) in DMF (19 ml) over 5 minutes. This solution was then heatedat 68° C. for 20 hours and the solvent was removed in vacuo. Theresulting concentrate was diluted with water (100 ml) and extracted withfour times with ethyl acetate which was washed with brine and dried withsodium sulphate. Filtration and evaporation of solvent gave a yellow oil(6.41 g). Tlc analysis (silica gel, 1:1 CHCl₃:CH₃OH) indicated a majorcomponent with R_(f) 0.21 and some impurities at the solvent front. Thisoil was kugelrohr distilled and the major fraction was collected at (airbath temperature) 132-143° C. at 400 mtorr to give the title compound;¹H nmr δ 2.35 (s, 3H), 3.81 (s, 3H), 3.82-3.92(m, 1H), 6.75-6.77 (d,1H), 7.12-7.17 (t, 1H), 7.42-7.45 (d, 1H).

A solution of the above base (4.44 g) in ethanol (44 ml), was treatedwith saturated ethanolic HCl (44 ml). While stirring, diethyl ether (120ml) was added portionwise, resulting in the slow separation of a whitesolid. After standing this solid was collected by filtration and driedat 62° C. in vacuo to yield the dihydrochloride salt of the titlecompound (5.53 g) mp 172.2-176.6° C. Anal; Calcd. forC₁₇H₂₆N₂O.2HCl.0.5H₂O: C, 57.30; H, 8.20; N, 7.86; Cl, 19.90. Found: C,57.44; H, 8.50; N, 7.36; Cl, 20.00.

1-Chloro-5-methoxy-1,2,3,4-tetrahydronaphthalene was prepared asfollows:

A 3-necked flask equipped with a condenser, addition funnel, mechanicalstirrer and under an inert atmosphere was charged with5-methoxy-1,2,3,4-tetrahydro-1-naphthol (8.70 gm; 48.8 mmol) [availablecommercially and also via reduction of 5-methoxy-1-tetralone] in drydiethyl ether (145 ml). Pyridine (1.0 g) was added while stirring atroom temperature. A solution of thionyl chloride (19.6 ml; 268 mmol) inether (52 ml) was then added dropwise in 10 minutes and stirringcontinued overnight. The reaction mixture was then poured into ice-water(500 ml) and the organic phase was separated. The aqueous phase wasextracted once more with diethyl ether and the combined organic extractwas dried with sodium sulphate. Filtration and removal of solvent invacuo gave a yellow solid (9.60 g). This material was used withoutfurther purification.

EXAMPLE 8 N-(5-Methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A 500 ml 3-necked flask equipped with a condenser, nitrogen inlet,thermometer and mechanical stirrer was charged with homopiperazine (64.4gm; 643 mmol) and DMAC (150 ml). Potassium iodide (4.7 g) was addedfollowed by the addition in one portion of a solution of1-chloro-5-methoxy-1,2,3,4-tetrahydronaphthalene (25.3 g; 129 mmol) inDMAC (100 ml). This solution was then heated overnight at 68° C. Aftertransferring the contents to a single-necked flask, the solvent wasremoved on a rotary evaporator under high vacuum using a water bath at40° C. The resulting concentrate was partitioned between water (400 ml)and ethyl acetate (400 ml) and the aqueous layer was again extractedseveral times with ethyl acetate, washed with brine and dried withmagnesium sulphate.

Filtration and evaporation of solvent gave a residue which by proton nmrwas free of the starting chloride. This residue was purified by columnchromatography on silica gel (1500 ml) with gradient elution (additionof 10% NH₄OH in methanol in increments to CH₂Cl₂) to yield the titlecompound (29 g). Tlc analysis (silica gel, 89:10:1 CH₂Cl₂:CH₃OH: NH₄OH)indicated a single component with R_(f) 0.38; ¹H nmr δ 3.81 (s, 3H,OCH₃), 3.90-4.04(m, 1H, benzylic CHN), 6.67-6.69 (d, 1H), 7.11-7.16 (t,1H), 7.41-7.45 (d, 1H).

EXAMPLE 9 S(+)N-(5-Methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

S(+) N-(5-Methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine wasobtained as the first material to elute on subjecting racemic material,prepared as in Example 8, to preparative Chiral Pak AD HPLC resolutionusing a hexane/ethanol mixture with modification with diethylamine. Theenantiomeric purity was determined on an analytical scale usinghexane:ethanol:diethylamine (97.5:2.5:0.1, v/v) and detection at 220 nm.The solution containing this enantiomer was concentrated using a rotaryevaporator to give the title compound (2.42 g), [α]_(D) ²²+88.4°(c=1.07, methanol); 98.4% ee.

To a solution of this base (1.0 g; 4.35 mmol) in ethanol (10 ml) wasadded by pipette a solution of maleic acid (1.0 g) in ether (35 ml)which resulted in the formation of a gum. Trituration afforded a whiteprecipitate. This solid was collected by filtration and dried in adrying pistol (50° C., 100 mtorr) to yield the dimaleate salt of thetitle compound (1.57 g), mp 113.5-115.5° C. Anal. Calcd. forC₁₆H₂₄N₂O.2C₄H₄O₄.0.5H₂O: C, 56.43; H, 6.79; N, 5.72. Found: C, 56.56;H, 6.53; N, 5.29.

EXAMPLE 10 S(+)1-Methyl-4-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A dry 100 ml 3-necked flask equipped with a condenser, addition funneland magnetic stirring bar was charged with lithium aluminum hydride(0.45 g; 11.8 mmol) and dry THF (15 ml) under a nitrogen atmosphere.S(+)N-Carbethoxy-N′-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine(1.65 g; 5.0 mmol) in THF (15 ml) was added dropwise and the solutionwas heated to reflux for 2.5 hours and cooled to ambient temperature.Saturated sodium sulphate (15 ml) was added dropwise at a rate amenableto maintaining control of the reaction and the content of the flask wasfiltered through diatomaceous earth and dried (MgSO₄). Filtration andremoval of solvent in vacuo gave a yellow oil (1.15 g) which waskugelrohr distilled to give the title compound (1.05 g), bp (air bathtemperature) 110-120° C. at 90 mtorr, homogeneous by tlc (silica gel,CH₃OH:CH₂Cl₂:NH₄OH 10:89:1), R_(f) 0.27; ¹H-nmr δ 2.36 (s, 3H),3.80-3.86 (OCH₃ and benzylic CHN), 6.66-6.68 (d, 1H), 7.10-7.16 (t, 1H),7.41-7.44(d, 1H); [α]_(D) ²²+69.1° (c=0.825, methanol).

To a solution of the base (0.91 g) in ethanol (25 ml) was added bypipette a solution of maleic acid (1.0 g) in ether (40 ml). Uponcompletion of the addition. a white precipitate formed. This solid wascollected by filtration and was dried overnight in a drying pistol (50°C. at 100 mtorr) to yield the dimaleate salt of the title compound (1.69g), mp 125.5-126; ¹H-nmr (300 MHz, CD₃OD) δ 6.26-6.31 (CH═CH, maleicacid), 6.75-6.77 (1H), 7.12-7.17 (1H), 7.29-7.33 (1H): [α]_(D) ²²+41°(c=0.245, methanol). Anal: Calcd. for C₁₇H₂₆N₂O.2C₄H₄O₄: C, 59.29; H,6.76; N, 5.53. Found C, 59.51; H, 7.06; N, 5.39. S(+)N-Carbethoxy-N′-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazinewas obtained as follows:

A dry 100 ml 3-necked flask equipped with a condenser, addition funneland magnetic Stirring bar under a nitrogen atmosphere was charged withS(+) N-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine (1.3g; 5.0 mmol) and methylene chloride (19 ml). Triethylamine (0.90 ml;6.45 mmol) was added and the flask was cooled in a Dry Ice/acetone bath.Ethyl chloroformate (0.55 ml; 5.75 mmol) in methylene chloride (10 ml)was added dropwise and the mixture was allowed to warm to ambienttemperature slowly. After stirring overnight, the content of the flaskwas partitioned between water and methylene chloride, the organic phasewas washed with brine and the solution was dried with magnesiumsulphate. Filtration and removal of solvent gave an yellow oil (1.67 g),homogeneous by tlc (silica gel, ethyl acetate), R_(f) 0.74; ¹H-nmr δ1.23-1.28 (t, OCH₂CH₃), 3.81 (s, OCH₃), 4.11-4.18 (q, OCH₂CH₃),6.67-6.69 (d, 1H), 7.10-7.16 (t, 1H), 7.36-7.39(d, 1H).

EXAMPLE 11 R(−)N-(5-Methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

R(−) N-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine wasobtained as the second material to elute on subjecting racemic material,prepared as in Example 8, to preparative Chiral Pak AD HPLC resolutionusing a hexane/ethanol mixture with modification with diethylamine. Thesolution containing this enantiomer was concentrated using a rotaryevaporator to give the title compound (2.95 g).

EXAMPLE 12 R(−)1-Methyl-4-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A dry 100 ml 3-necked flask equipped with a condenser, addition funneland magnetic stirring bar was charged with lithium aluminum hydride(0.30 g; 7.90 mmol) and dry THF (10 ml) under a nitrogen atmosphere.R(−)Carbethoxy-N′-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine(1.25 g; 3.26 mmol) in THF (15 ml) was added dropwise and the solutionwas heated to reflux for 2.5 hours and cooled to ambient temperature.Saturated sodium sulphate (10 ml) was added dropwise at a rate amenableto maintaining control of the reaction and the content of the flask wasfiltered through diatomaceous earth and dried (MgSO₄). Filtration andremoval of solvent in vacuo gave an oil (0.90 g) which was kugelrohrdistilled to give the title compound (0.74 g), bp (air bath temperature)125-140° C. at 80 mtorr, homogeneous by tlc (silica gel,CH₃OH:CH₂Cl₂:NH₄OH 10:89:1); ¹H-nmr δ 2.36 (s, 3H), 3.82-3.88 (OCH₃ andbenzylic CHN), 6.66-6.69 (d, 1H), 7.11-7.16 (t, 1H), 7.42-7.45(d, 1H);[α]_(D) ²²−66.6° (c=0.72, methanol).

To a solution of the base (0.73 g) in ethanol (10 ml) was added bypipette a solution of maleic acid (0.80 g) in ether (40 ml). Uponcompletion of the addition, a white precipitate formed. This solid wascollected by filtration and was dried overnight in a drying pistol (50°C. at 90 mtorr) to yield the dimaleate salt of the title compound (1.17g), mp 124.8-125.4; ¹H-nmr (300 MHz, CD₃OD) δ 4.02 (s, 3H), 6.52 (4H,CH═CH maleic acid), 6.99-7.01 (1H), 7.36-7.41 (1H), 7.55-7.58 (1H):Anal: Calcd. for C₁₇H₂₆N₂O.2C₄H₄O₄: C, 59.29; H, 6.76; N, 5.53. Found:C, 59.39; H, 7.01; N, 5.39. R(−)N-Carbethoxy-N′-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazinewas obtained as follows:

A dry 100 ml 3-necked flask equipped with a condenser, addition funneland magnetic stirring bar under a nitrogen atmosphere was charged withR(−) N-(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine (1.8g; 6.92 mmol) and methylene chloride (15 ml). Triethylamine (1.30 ml;9.32 mmol) was added and the flask was cooled in a Dry Ice/acetone bath.Ethyl chloroformate (0.80 ml; 8.37 mmol) in methylene chloride (10 ml)was added dropwise and the mixture was allowed to warm to ambienttemperature slowly. After stirring overnight, the content of the flaskwas partitioned between water and methylene chloride, the organic phasewas washed with brine and the solution was dried with magnesiumsulphate. Filtration and removal of solvent gave a brown oil (2.10 g).This material was purified by column chromatography on silica gel withethyl acetate elution to give an amber oil (1.3 g); ¹H-nmr δ1.23-1.28(t, OCH₂CH₃), 3.81 (s, OCH₃), 4.11-4.18 (q, OCH₂CH₃), 6.67-6.70 (d, 1H),7.08-7.16 (t, 1H), 7.38-7.40(d, 1H). [α]_(D) ²²−59.5° (c=0.92,methanol).

EXAMPLE 131-Isopropyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A 100 ml 3-necked flask under nitrogen atmosphere was chargedsequentially with N-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine(0.73 g; 3.2 mmol) in THF (20 ml), methanol (10 ml) and acetone (3.3 ml;45 mmol). To this stirred solution, sodium cyanoborohydride (0.30 g;4.75 mmol) was added as a solid followed by acetic acid (0.24 ml; 4.2mmol). After stirring at ambient temperature for 45 minutes, tlcanalysis (silica gel, 9:1 CHCl₃:CH₃OH) of an aliquot revealed theabsence of starting amine (R_(f) 0.03) and the presence of a majorcomponent with R_(f) 0.16. The content of the flask was thenconcentrated in vacuo. The residue was treated with aqueous sodiumbicarbonate and extracted several times with ethyl acetate which wasthen dried with sodium sulphate. Filtration and removal of solvent invacuo gave an oil which was subjected to high vacuum for four hours atambient temperature to yield the title compound (0.87 g); tlc (ibid),homogeneous, R_(f) 0.16; ¹H nmr δ 1.01-1.05 (6H), 3.88-3.92 (m, 1H),6.98-7.22 (m, 3H), 7.77-7.79 (1, H). Anal: Calcd. for C₁₈H₂₈N₂; C,79.36; H, 10.36; N, 10.28. Found: C, 79.46; H, 10.12; N, 10.08.

The above base (0.67 g) was dissolved in ethanolic HCl (7 ml) and wastreated with ether (˜45 ml) portionwise to the cloud point. On standing,only a gum separated. Trituration resulted in the formation of a whitesolid which was collected by filtration and dried in vacuo (65° C. at 20mtorr) to give the dihydrochloride salt of the title compound (0.66 g),mp 149.5-151° C. (hygroscopic). Anal: Calcd. for C₁₈H₂₈N₂.2HCl.0.66H₂O:C, 58.06; H, 8.93; N, 7.52. Found: C, 58.11; H, 8.87; N, 7.30.

EXAMPLE 14 S(+)1-Isopropyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A 25 ml 3-necked flask under nitrogen atmosphere was chargedsequentially with S(+)N-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine (0.30 g; 1.3 mmol)in THF (8 ml), methanol (4 ml) and acetone (1.1 ml; 18 mmol). To thisstirred solution, sodium cyanoborohydride (0.12 g; 2.0 mmol) was addedas a solid followed by acetic acid (0.10 ml; 1.8 mmol). After stirringat ambient temperature for 45 minutes, tlc analysis (silica gel, 9:1CHCl₃:CH₃OH) of an aliquot revealed the absence of starting amine. Thecontent of the flask was then concentrated in vacuo. The residue wastreated with aqueous sodium bicarbonate and extracted several times withethyl acetate which was then dried with sodium sulphate. Filtration andremoval of solvent in vacuo gave an oil (0.50 g) which was kugelrohrdistilled to yield the title compound (0.31 g), bp (air bathtemperature) 148-152° C. at 160 mtorr; tlc (ibid), R_(f) 0.18. [α]_(D)²²+80° (c=1.00, methanol).

The above base (0.25 g) was dissolved in ethanol (5.5 ml) and wastreated with a saturated solution of maleic acid in ether (11 ml) andleft at ambient temperature. On prolonged standing, a solid very slowlyseparated. This was collected by filtration and dried in vacuo (65° C.at 20 mtorr) to give the dimaleate salt of the title compound (0.28 g),mp 115.5-116.2° C. Anal: Calcd. for C₁₈H₂₈N₂.2C₄H₄O₄: C, 61.89; H, 7.19;N, 5.55. Found: C, 61.44; H, 7.16; N, 5.52.

EXAMPLE 15 N-(6-Fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperzine

Under nitrogen atmosphere, a 3-necked 500 ml round-bottomed flask wascharged with homopiperazine (20 mg), DMF (130 ml) and potassium iodide(0.35 g). A solution of 7.70 g (41.7 mmol) of1-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene in 39 ml of DMF wasadded over a five minute period. The mixture was stirred at 55°-60° C.for two hours and then at ambient temperature overnight. Tlc analysis onsilica gel (diethyl ether:hexane 5:95) showed the absence of thestarting halide, R_(f) 0.77. Most of the DMF was then removed in vacuo(35° C., 0.6 torr) using a rotary evaporator. The residue was treatedwith 300 ml of water and extracted with ethyl acetate which was thendried (MgSO₄). Filtration and removal of solvent in vacuo gave a yellowoil which was kugelrohr distilled to give the title compound, (8.63 g),bp (air bath temperature) 155°-166° C. at 0.26 torr, as a viscous yellowoil. ¹H NMR (300 MHz, CDCl₃) δ 3.86 (t, 1H, ArCHN), 6.78 (dd, 1H), 6.85(m, 1H), 7.75 (m, 1H). Anal: Calcd. for C₁₅H₂₁FN₂: C, 72.55; H, 8.52; N,11.28. Found: C, 72.05; H, 8.53; N. 10.95.1-Chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene was prepared as follows:

To a solution of 7.02 g (42.2 mmol) of6-fluoro-1,2,3,4-tetrahydro-1-naphthol and 0.92 ml of pyridine in 130 mlof ether under nitrogen was added 16.9 ml (232 mmol) of thionyl chloridein 44 ml of ether over ten minutes. After stirring overnight at ambienttemperature, tlc analysis on silica gel (ether:hexane 5:95) indicatedthe absence of the starting alcohol. The mixture was added to 200 g ofice, diluted with more ether and the ether extract was washed with waterand brine and dried (MgSO₄). Filtration and removal of the solventinvacuo gave 7.73 g of a yellow oil. Tlc analysis indicated a majorcomponent at R_(f) 0.77 and a minor component at R_(f) 0.85. ¹H NMR (300MHz, CDCl₃) δ 5.3 (t, 1H, ArCHCl), 7.4 (m, 1H), 6.85 (m, 1H), 6.78 (dd,1H). A minor amount of 3,4-dihydro-6-fluoronaphthalene was indicated asthe impurity. This material was used without further purification.

EXAMPLE 161-Methyl-4-(6-fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A 20 ml round bottom flask under nitrogen atmosphere was charged with0.47 g (1.9 mmol) of the homopiperazine prepared in Example 15, 1.2 mlof water and 0.92 ml of 98% formic acid. After stirring for fiveminutes, 0.34 ml (4.6 mmol) of 37% formaldehyde was added and themixture was heated in an oil bath at 70° C. After one hour tlc analysison silica gel (CHCl₃:CH₃OH 95:5) indicated the absence of the startingamine (R_(f), origin) and components with R_(f)s 0.10 . 0.72 and 0.95.The mixture was diluted with water and extracted several times withether. The aqueous extract was made alkaline with solid potassiumcarbonate and extracted with ethyl acetate which was dried (MgSO₄).Filtration and removal of solvent in vacuo gave 45 mg of an oil (lowerR_(f)). ¹H NMR (300 MHz, CDCl₃) δ 2.34 (s, 3H), 3.82 (t, 1H, ArCHN),6.75 (dd, 1H), 6.85 (m, 1H) 7.73 (t, 1H).

This material in 1.4 ml of ethanol was treated with 2.8 ml of asaturated solution of maleic acid in diethyl ether. Since no precipitateformed on standing, the solution was concentrated to give a gum.Trituration with ether and decantation resulted in the formation of asolid which was dried in vacuo at 55° C. to give 39 mg, mp 78.8°-79.5°C. Anal: Calcd. for C₁₆H₂₃FN₂.2C₄H₄O₄.0.75H₂O: C, 56.74; H, 6.45; N.5.51. Found: C, 56.88; H, 6.32; N, 5.28.

EXAMPLE 17 S(+)N-(6-Fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

S(+) N-(6-Fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine wasobtained as the first material to elute on subjecting racemic material(approximately 3.5 g), prepared as in Example 15, to preparative ChiralPak AD HPLC resolution using a hexane/ethanol mixture with modificationwith diethylamine. The enantiomer purity was determined on an analyticalscale using hexane:ethanol:diethylamine (90:10:0.10, v/v) and detectionat 220 nm. The solution containing this enantiomer was concentratedusing a rotar evaporator. The residue was kugelrohr distilled to give1.4 g of a colorless oil, bp (air bath temperature) 110°-120° C. at 120mtorr, [α]_(D) ²²+93.5° (c=1.46, methanol); >99% ee. Anal: Calcd. forC₁₅H₂₁FN₂: C, 72.55; H, 8.52; N, 11.28. Found: C, 72.14; H, 8.44; N,11.11.

EXAMPLE 18 S(+)1-Methyl-4-(6-fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

S(+)N-Carbethoxy-N′-(6-fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine(1.30 g: 4.00 mmol) was reduced with lithium aluminum hydride (0.32 g; 8mmol) in THF as in Example 4. The yellow oil was kugelrohr distilled togive the title compound (0.88 g), bp (air bath temperature) 125° C. at150 mtorr., homogeneous by tlc (silica gel, CH₃OH:CH₂Cl₂:NH₄OH 10:89:1),R_(f) 0.44; [α]_(D) ²²+92.1° (c=0.467, methanol). A solution of thismaterial in 5 ml of ethanol was treated with saturated ethereal HCl toform a white solid which was collected by filtration and dried in vacuo(65° C., 200 mtorr) overnight to give 1.04 g, mp 230.6°-231.6° C. Anal:Calcd. for C₁₆H₂₃FN₂.2HCl.0.1H₂O: C, 57.00; H, 7.53: N, 8.31. Found: C,56.73; H, 7.41; N, 7.94. S(+)N-Carbethoxy-N′-(6-fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazinewas obtained as follows:

S(+) N-(6-fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine (1.0g; 4.03 mmol), triethylamine (0.70 ml; 5.02 mmol) and ethylchloroformate (0.50 ml; 5.2 mmol) were reacted in methylene chloride asin Example 4 to give a yellow oil (1.30 g), homogeneous by tlc (silicagel, ethyl acetate), R_(f) 0.83; ¹H NMR (300 MHz, CDCl₃) δ 4.11-4.18 (q,2H, OCH₂CH₃).

EXAMPLE 19 R(−)N-(6-Fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

R(−) N-(6-Fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine wasobtained as the second material to elute on subjecting racemic material,prepared as in Example 15, to preparative Chiral Pak AD HPLC resolutionusing a hexane/ethanol mixture with modification with diethylamine. Theenantiomeric purity was determined on an analytical scale usinghexane:ethanol:diethylamine (90:10:0.10, v/v) and detection at 220 nm.The solution containing this enantiomer was concentrated using a rotaryevaporator and the residue was kugelrohr (as in example 17) to give thetitled compound (1.38 g), [α]_(D) ²²−88.6° (c=2.01, methanol); >99% ee.Anal: Calcd. for C₁₅H₂₁FN₂: C, 72.55; H, 8.52; N, 11.28. Found: C,72.05; H, 8.46; N, 11.13.

EXAMPLE 20 R(−)1-Methyl-4-(6-fluoro-1,2,34-tetrahydro-1-naphthalenyl)homopiperazine

In an analogous method to Example 18, R(−)N-Carbethoxy-N′-(6-fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine(1.60 g) in THF (15 ml) was reacted with lithium aluminium hydride (0.40g) in THF (15 ml). Additional 0.85 g of lithium aluminium hydride wasadded to complete the reaction. Kugelrohr distillation gave the titlecompound (1.053 g), bp (air bath temperature) 110° C. at 100 mtorr;[α]_(D) ²²−85.3° (c=1.77, methanol).

Treatment of a solution of 1.0 g of this base in 7 ml of ethanol withsaturated ethereal HCl resulted in the formation of a white solid whichwas collected by filtration and dried invacuo (61° C., 100 mtorr)overnight to give 1.12 g, mp 229°-230° C. Anal: Calcd. forC₁₆H₂₃FN₂.2HCl: C, 57.32; H, 7.52: N. 8.35. Found: C, 56.92; H, 7.35; N,8.60. R(−)N-Carbethoxy-N′-(6-fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazinewas obtained from R(−)N-(6-fluoro-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine (1.3 g) ina manner analogous to that of Example 18, giving a viscous oil (1.6 g),homogeneous by tlc (silica gel. ethyl acetate). ¹H NMR δ 4.11-4.18 (q,2H, OCH₂CH₃).

EXAMPLE 211-Methyl-4-(6-bromo-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

N-Methylhomopiperazine (2.31 g; 20.2 mmol) and potassium iodide (0.35 g;2.2 mmol) in DMF (13 ml) were reacted with1-chloro-6-bromo-1,2,3,4-tetrahydronapthalene (2.48 g; 10.1 mmol) in DMF(8 ml) as in Example 15. The yellow oil was kugelrohr distilled to givethe title compound, 1.47 g, bp (air bath temperature) 152°-165° C. at0.10 torr; ¹H NMR (300 MHz, CDCl₃) δ 2.38 (s, 3H, NCH3), 3.81 (t, 1H,ArCHN), 7.19 (s, 1H), 7.25 (d, 1H), 7.64 (d, 1H). Anal: Calcd. forC₁₆H₂₃BrN₂: C, 59.45; H, 7.17; N, 8.67. Found: C, 59.40; H, 7.02; N,8.30. 1-Chloro-6-bromo-1,2,3,4-tetrahydronaphthalene was prepared asfollows:

A solution of 6-bromo-1,2,3,4-tetrahydro-1-naphthol (7.10 g; 31.3 mmol)and pyridine (0.68 ml) in ether (95 ml) under nitrogen was treated withthionyl chloride (12.6 ml; 172 mmol) in ether (33 ml) as in Example 15to give a yellow oil (7.3 g). Tlc analysis (ibid) indicated a majorcomponent at R_(f) 0.68 and a very minor component at R_(f) 0.73; ¹H NMR(300 MHz, CDCl₃) δ 5.24 (m, 1H, ArCHCl), 7.19-7.30 (3H). A minor amountof 3,4-dihydro-6-bromonaphthalene was indicated as an impurity. Thismaterial was used without further purification.6-Bromo-1,2,3,4-tetrahydro-1-naphthol was prepared as follows:

A one liter three-necked roundbottom flask under a nitrogen atmospherewas charged with 1.07 g (49.1 mmol) of lithium borohydride and 106 ml ofether and the stirred suspension was cooled to −75° C. (DryIce/acetone). A solution of 7.0 g (31.1 mmol) of 6-bromo-1-tetralone in336 ml of ether was added over a 15 minute period and the mixture wasallowed to warm to 0° C. Additional lithium borohydride, 0.6 g (27mmol), was added and stirring continued at 0° C. for another fifteenminutes at which time tlc analysis on silica gel (ether:hexane 1:4)indicated a major component with R_(f) 0.21 and absence of the startingketone (R_(f) 0.45). Ice was added to the mixture which was then stirredovernight. The ether phase was separated, dried (MgSO4) and concentratedinvacuo to give 7.04 g of a colorless oil which solidified. ¹H NMR (300MHz, CDCl₃) δ 1.7-2.1 (m, 4H), 2.66-2.83 (m, 2H), 4.72 (t, 1H, ArCHOH),7.26 (s, 1H), 7.31 (over lapping singlets, 2H).

EXAMPLE 22 N-(6-Bromo-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A solution of of homopiperazine (2.96 g; 29.6 mmol) and potassium iodide(0.05 g; 0.28 mmol) in DMF (17 ml) was treated with1-chloro-6-fluoro-1,2,3,4-tetrahydronapthalene (1.45 g; 5.91 mmol) inDMF (5 ml) as in Example 15. Kugelrohr distillation gave the titlecompound as a yellow oil, 0.98 g, bp (air bath temperature) 165°-180° C.at 0.10 torr; homogeneous by tlc on silica gel (CHCl₃:CH₃OH 9:1), R_(f)0.07; ¹H NMR (300 MHz, CDCl₃) δ 2.97 (t, 2H, ArCH2), 3.81 (t, 1H,ArCHN), 7.19 (s, 1H), 7.25 (dd, 1H), 7.66 (d, 1H). Anal: Calcd. forC₁₅H₂₁BrN₂: C, 58.26; H, 6.84; N, 9.06. Found: C, 58.30; H, 6.58; N,8.21.

EXAMPLE 231-Methyl-4-(6-formyl-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

Under nitrogen atmosphere, a dry 3-necked 50 ml round-bottomed flask wascharged with 2.31 g (20.2 mmol) of1-methyl-4-(6-bromo-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine and8 ml of anydrous THF and was cooled to −75° C. (Dry Ice/acetone). Tothis solution was added dropwise 4.1 ml (6.9 mmol, 2.18 equivalents) oft-butyllithium (1.7M solution in pentane) over a ten minute period,followed by stirring for an additional ten minutes. Anhydrous DMF, 25ml, was added rapidly resulting in the temperature rising to −40° C. Thesolution was again cooled to −75° C. and was allowed to spontaneouslywarm to room temperature. The content of the flask was added to waterand acidified with 1N HCl to pH 2. After five minutes this solution wasmade alkaline with potassium carbonate and extracted several times withether. The combined ether extract was dried (MgSO₄), filtered andconcentrated invacuo to yield 0.82 g of a yellow oil. Proton NMRanalysis (300 MHz) indicated that this material was a 6:1 mixture of thetitle compound and1-methyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine. A portion,0.41 g, was subjected to kugelrohr distillation with temperaturemaintained at 100°-102° C. at 0.06 torr. This resulted in a distillatewhich was a mixture of the two components. The residual material was thepure title compound, 0.33 g; ¹H-NMR (300 MHz, CDCl₃) δ 3.88-3.93 (m, 1H,ArCHN), 7.56 (s, 1H), 7.65-7.68 (d, 1H), 7.97-8.02 (d, 1H), 9.50 (s, 1H,CHO).

EXAMPLE 241-Methyl-4-(6-vinyl-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A dry flask under nitrogen was charged with 0.25 g (0.69 mmol) ofmethyltriphenyl phosphonium bromide and 2.1 ml of anhydrous THF. To thissuspension at ambient temperature was added 0.30 ml (0.69 mmol) of a 2.3M solution of n-butyllithium in hexane. This was followed by theaddition of a solution of 0.18 g (0.67 mmol) of1-methyl-4-(6-formyl-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine in1.4 ml THF. After two hours, analysis by ¹H-NMR of a worked-up aliquotrevealed the presence of the desired product (vinyl proton resonances)as well as residual aldehyde (CHO resonance). A second portion of thetriphenylphosphonium ylid (0.070 mmol) was generated in 4 ml THF andadded to the mixture containing the residual aldehyde. After four hours,analysis by ¹H-NMR of a worked-up aliquot indicated only a trace ofaldehyde. The reaction mixture was concentrated invacuo to semisolidwhich was treated with water and extracted several times with ether. Thecombined ether extract was dried (MgSO₄), filtered and concentratedinvacuo to a semisolid, 0.34 g. This material was triturated withhexane, filtered and the hexane was removed invacuo. The resultingresidue was again titurated with hexane, filtered and concentratedinvacuo to give the title compound, 0.18 g, as a yellow oil; ¹H-NMR(300Hz, CDCl₃) δ 5.17-5.20 (1H, d), 5.68-5.74 (1H, d), 6.62-6.71 (1H, q).

EXAMPLE 251-Methyl-4-(6-ethyl-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine

A solution of 0.17 g of1-methyl-4-(6-vinyl-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine in2 ml of THF was hydrogenated at atmospheric pressure using 0.08 g of 10%Palladium-on-carbon as catalyst. After five hours, the mixture wasfiltered and the solvent was removed invacuo. Kugelrohr distillation ofthis oil gave 0.14 g of a colorless oil, bp (air bath temperature)116°-122° C. at 40 mmtorr, essentially homogeneous by tlc on silca gel(CHCl₃:CH₃OH 9:1). R_(f) 0.15.

A portion of this material, 0.083 g, in 2.5 ml of ethanol was treateddropwise with 5.5 ml of a saturated solution of maleic acid in diethylether to form a precipiate. This heterogeneous solution was diluted with4 ml of diethyl ether and was left at ambient temperature overnight. Thewhite solid was collected by filtration, washed with ether and driedinvacuo to give 0.050 g, mp 131.5°-132.8° C.; ¹H-NMR (300 MHz, d₆-DMSO)δ 1.31-1.81(t, 3H, CH₃CH₂), 2.89 (s, 3H, NCH₃), 3.91 (1H, ArCHN), 6.14(s, 4H, CH═CH, maleic acid), 6.90 (s, 1H), 6.98-7.00 (d, 1H), 7.59-7.61(d, 1H). Anal: Calcd. for C₁₈H₂₈N₂.2C₄H₄O₄: C, 61.89; H, 7.19; N, 5.55.Found: C, 61.51; H, 7.08; N, 5.51.

EXAMPLE 26 R(−)N-Isopropyl-N′-(1,2,3,4-tetrahydronaphthalen-4-yl)homopiperazine

R(−) N-(1,2,3,4-tetrahydronaphthalen4-yl)homopiperazine (2.00 g; 8.7mmol) in THF (50 ml), methanol (25 ml) and acetone (15.5 ml; 174 mmol)was reacted with sodium cyanoborohydride (1.1 g; 17.6 mmol) and aceticacid (1.0 ml) as in Example 14. Kugelrohr distillation gave the titlecompound (2.29 g), bp (air bath temperature) 165-175° C. at 180 mtorr;[α]_(D) ²²−74° (c=0.64, methanol).

The above base (2.25 g) was dissolved in ethanol (10 ml) and was slowlytreated with a dispersion of 2.25 g (19.3 mmol) of maleic acid in ether(100 ml), resulting in the formation of a gum. The ether was decantedand the residue was triturated with fresh ether to get a solid. This wascollected by filtration and dried invacuo (60° C. at 150 mtorr) to givethe dimaleate salt of the title compound (2.55 g), mp 105-106° C.; ¹HNMR (300 MHz, d₆-DMSO) δ 1.23-1.25 (d, 6H), 6.10 (4H, CH═CH, maleicacid). Anal: Calcd. for C₁₈H₂₈N₂.2C₄H₄O₄: C, 61.89; H, 7.19; N, 5.55.Found: C, 61.44; H, 7.14; N, 5.54.

EXAMPLE 271-(1,2,3,4-Tetrahydronaphthyl)-4-(3-methylbutyl)homopiperazine

A 250 mL flask was charged with a solution of1-(1,2,3,4-tetrahydronaphthyl)homopiperazine (2.68 g, 11.6 mmol) in THF(105 mL). Triethylamine (2.20 ml, 3.03 g, 29.9 mmol) and1-bromo-3-methylbutane (2.00 ml, 1.59 g, 10.5 mmol) were added. Thesolution was immersed in a 60° C. oil bath for 16 hours during whichtime a precipitate formed. The resulting mixture was filtered and thefiltrate was concentrated to give an orange oil. This crude product waspurified by column chromatography using diethyl ether:hexane:methanol(5:5:1) to obtain the title compound as a yellow oil (2.34 g). ¹H NMR(CDCl₃, 300 MHz) δ 0.89 (d, 6H), 1.39 (m, 2H), 1.54-1.79 (m, 5H),1.92-2.15 (m, 2H), 2.50 (m, 2H), 2.60-2.80 (m, 10H), 3.90 (m, 1H),7.02-7.18 (m, 3H), 7.77 (d, 2H); m/s: M+H⁺ 301.

EXAMPLES 28-51

By the method of Example 27, substituting the corresponding bromocompound for 1-bromo-3-methylbutane the following compounds wereprepared, wherein (R) and (S) refer o the stereochemistry at the1-position of the 1,2,3,4-tetrahydronaphthyl ring.

m/s Examples R NMR M + H⁺ 28

7.76 (d 1H), 7.39-7.11 (m, 8H), 3.57 (t. 1H), 3.16 (t, 1H), 2.91 (t,1H), 2.81-2.72 (m, 7H), 1.87 (m, 1H), 1.83 (m, 2H), 1.79 (m, 1H), 1.64(m, 2H), 1.16 (m, 2H) 335 29¹

7.75 (d, 1H), 7.31-7.03 (m, 8H), 3.91 (m, 1H), 2.95 (t, 2H), 2.85-2.72(m, 14H), 1.98 (m, 2H), 1.86 (m, 2H), 1.64 (m, 2H) 349 30^(2,3)

7.46 (d, 1H), 7.22-6.98 (m, 3H), 3.88 (m, 1H), 3.85 (s. 2H), 2.83-2.65(m, 10H), 1.98 (m, 2H), 1.76 (m, 2H), 1.63 (m, 2H) 411 31¹

8.14 (d, 2H), 7.53 (d, 1H), 7.36 (d, 2H), 7.18- 7.03 (m, 3H), 3.92 (m,1H), 2.91-2.68 (m, 14H), 1.98 (m, 2H), 1.81 (m, 2H), 1.63 (m, 2H) 38032⁴

7.82 (d,1H), 7.18-7.01 (m, 6H), 3.92 (m, 1H), 3.70 (s, 2H), 2.82-2.66(m, 10H), 2.07-1.93 (m, 2H), 1.78 (m, 2H), 1.66 (m, 2H) 357 33⁵

7.72 (d, 1H), 7.17-7.08 (m, 3H), 3.88 (m, 3H), 2.83 (m, 2H), 2.75-2.66(m, 6H), 1.99 (m, 2H), 1.77 (m, 2H), 1.64 (m, 2H), 1.43 (m, 2H) 461 34¹

7.88 (d, 1H), 7.80 (d, 1H), 7.59 (d, 1H), 7.50 (t, 1H), 7.29 (t, 1H),7.19-6.98 (m, 3H), 3.93 (m, 1H), 3.83 (s, 2H), 2.82-2.66 (m, 10H), 1.96(m, 2H), 1.76 (m, 2H), 1.64 (m, 2H) 389 35

7.82 (d, 1H), 7.34-7.26 (m, 4H), 7.17-7.02 (m, 3H) 3.89 (m, 1H), 3.66(s, 2H), 2.83-2.62 (m, 10H), 2.08-1.95 (m, 2H), 1.86-1.75 (m, 2H),1.68-1.58 (m, 2H), 1.31 (s, 9H) 377 36

7.89 (d, 1H), 7.48-7.26 (m, 5H), 7.25 (d, 2H), 7.16-6.95 (m, 3H), 6.92(d, 2H), 5.05 (s, 2H), 3.88 (m, 1H), 3.60 (s, 2H), 2.81-2.60 (m, 10H),2.02 (m, 2H), 1.77-1.58 (m, 4H) 427 37^(1,6) —Et 7.73 (d, 1H), 7.19-7.04(m, 3H), 3.91 (m, 1H), 259 2.91 (m, 2H), 2.85-2.67 (m, 10H), 2.08-1.88(m, 4H), 1.63 (m, 2H), 1.17 (t, 3H) 38⁷ -n-Pr 7.74 (d, 1H), 7.20-7.00(m, 3H), 3.90 (m, 1H), 273 2.85 (m, 2H), 2.74 (m, 8H), 2.57 (m, 2H),1.96 (m, 4H), 1.68-1.53 (m, 4H), 1.26 (t, 3H) 39⁷ -n-Bu 7.80 (d, 1H),7.18-6.91 (m, 3H), 3.93 (m, 1H), 287 2.84-2.70 (m, 10H), 2.53 (t, 2H),2.53 (m, 2H), 2.02 (m, 2H), 1.81 (m, 2H), 1.64 (m, 2H), 1.61 (m, 2H)0.95 (t, 3H) 40^(8,4) -n-pentyl 7.73 (d, 1H), 7.22-7.11 (m, 3H), 3.89(m, 1H), 301 2.95 (m, 2H), 2.74 (m, 2H), 2.56 (m, 8H), 1.99 (m, 2H),1.86 (m, 2H), 1.68-1.54 (m, 4H), 1.30 (m, 4H), 0.89 (t, 3H) 41^(9,10)

7.66 (d, 1H), 7.08-6.92 (m, 3H), 3.78 (m, 1H), 2.77 (t, 2H), 2.73-2.56(m, 8H), 2.32 (d, 2H), 1.90 (m, 2H), 1.69 (m, 2H), 1.51 (m, 2H), 0.79(m, 1H), 0.39 (m, 2H), −0.14 (m, 2H) 285 42^(11,12)

7.70 (d, 1H), 7.21-7.11 (m, 3H), 3.90 (m, 1H), 2.93 (m, 2H), 2.76-2.52(m, 12H), 2.08-1.68 (m, 11H) 299 43^(13,14)

7.77 (d, 1H), 7.21-7.03 (m, 3H), 3.91 (m, 1H), 2.90-2.63 (m, 10H), 2.34(m, 2H), 2.01 (m, 2H), 1.81-1.72 (m, 2H), 1.69-1.58 (m, 2H), 1.33- 1.27(m, 9H), 0.87 (m, 6H) 343 44¹⁵

7.76 (d, 1H), 7.34-6.97 (m, 8H), 3.88 (m, 1H), 2.84-2.51 (m, 14H), 2.00(m, 2H), 1.83-1.61 (m, 6H) 349 45¹⁵

7.76 (d, 1H), 7.34-6.97 (m, 8H), 3.88 (m, 1H), 2.84-2.51 (m, 14H),2.00(m, 2H), 1.83-1.61 (m, 6H) 349 46¹⁶

7.77 (d, 1H), 7.18-7.03 (m, 3H), 3.90 (m, 1H), 2.85-2.65 (m, 10H), 2.58(m, 2H), 2.08-1.95 (m, 2H), 1.84 (m, 2H), 1.60 (m, 3H), 1.41 (m, 2H),0.89 (d, 6H) 301 47¹⁶

7.75 (d, 1H), 7.25-6.98 (m, 3H), 3.90 (m, 1H), 2.87-2.67 (m, 10H), 2.58(m, 2H), 1.99 (m, 2H), 1.84 (m, 2H), 1.61 (m, 3H), 1.43 (m, 2H), 0.90(d, 6H) 301 48^(13,17)

7.76 (d, 1H), 7.18-7.02 (m, 3H), 3.88 (m, 1H), 2.82-2.61 (m, 10H), 2.30(d, 2H), 2.00 (m, 2H), 1.74-1.61 (m, 4H), 1.39-1.21 (m, 9H), 0.86 (m,6H) 343 49^(13,18)

7.79 (d, 1H), 7.18-7.02 (m, 3H), 3.88 (m, 1H), 2.82-2.61 (m, 10H), 2.30(d, 2H), 2.01 (m, 2H), 1.74-1.62 (m, 4H), 1.38-1.19 (m, 9H), 0.87 (m,6H) 343 50¹⁶

8.10 (d, 1H), 7.62 (d, 2H), 7.45 (d, 2H), 7.18-6.98 (m, 3H), 3.90 (m,1H), 3.74 (m, 4H), 2.83-2.64 (m, 6H), 2.04 (m, 2H), 1.86 (m, 2H), 1.76(m, 2H), 1.64 (m, 2H) 389 51

7.78 (d, 1H), 7.37-7.20 (m, 5H), 7.17-7.02 (m, 3H), 3.88 (m, 1H), 3.64(s 2H), 2.85-2.63 (m, 10H), 2.00 (m, 2H), 1.76 (m, 2H) 1.62 (m, 2H) 321¹The product was not purified by column chromatography ²The reaction wascarried out by heating in a 40° C. oil bath for 16 hours. ³The solventused for column chromatography was 25% methanol in methylene chloride.⁴The solvent used for column chromatography was 25% ethyl acetate inhexane. ⁵The reaction was carried out at room temperature for 3 days.⁶The crude product was purified by the following procedure. The crudeproduct was dissolved in diethyl ether and washed with 1M NaOH and thensaturated NaCl. The organic layer was then dried over anhydrous MgSO₄,filtered and concentrated to give the product. ⁷The solvent used forcolumn chromatography was 50% ethyl acetate in hexane. ⁸The reaction wascarried out by heating in a 60° C. oil bath for 16 hours followed bystirring at room temperature for 16 hours. ⁹The reaction was carried outby heating in a 70° C. oil bath for 16 hours. ¹⁰The solvent used forcolumn chromatography was 5% methanol im methylene chloride. ¹¹Thereaction was carried out by heating in a 60° C. oil bath for 2 daysfollowed by stirring at room temperature for 2 days. ¹²The solvent usedfor column chromatography was a gradient from 25% to 50% ethyl acetatein hexane. ¹³The reaction was carried out by heating in a 70° C. oilbath for 2 days. ¹⁴The solvent used for column chromatography was 2.5%methanol in methylene chloride. ¹⁵The solvent used for columnchromatography was 1% methanol in diethyl ether:hexane (1:1). ¹⁶Thereaction was carried out by heating in a 70° C. oil bath for 4 hoursfollowed by stirring at room temperature for 16 hours. ¹⁷The solventused for column chromatography was 20% diethyl ether in hexane. ¹⁸Thesolvent used for column chromatography was 15% diethyl ether in hexane.¹⁹The reaction was carried out by heating in a 50° C. oil bath for 2hours followed by stirring at room temperature for 16 hours.

EXAMPLE 52 R1-(1,2,3,4-Tetrahydronaphthyl)-4-(2-methylpropyl)homopiperazine

A 50 mL flask was charged with R1-(1,2,3,4-tetrahydronaphthyl)-homopiperazine (1.12 g, 4.85 mmol) andisobutyric acid (12.8 g, 145 mmol). The flask was immersed in a 50° C.oil bath. After heating for 10 minutes, NaBH₄ was added in portions over15 minutes. After heating for 16 hours, the resulting mixture wasimmersed in an ice water bath and water (20 mL) was added. NaOH pelletswere added until the solution was strongly basic. The mixture was thenextracted with ethyl acetate (3×125 mL) and the combined extracts weredried over anhydrous MgSO₄, filtered and concentrated to give a yellowoil. This crude product was purified by simple distillation underreduced pressure using a short-path distillation apparatus (bp=121-126°C., 120 mtorr) to obtain the title compound as a colorless oil (1.19 g).¹H NMR (CDCl₃, 300 MHz) δ 0.89 (d, 6H), 1.58-1.76 (m, 5H), 1.93-2.08 (m,2H), 2.24 (d, 2H), 2.59-2.77 (m, 10H), 3.86 (m, 1H), 7.02-7.18 (m, 3H).777 (d, 1H); m/s: M+H⁺ 287.

EXAMPLES 53-57

By the method of Example 52, substituting the corresponding acidcompound for isobutyric acid the following compounds were prepared,wherein (R) and (S) refer to the stereochemistry at the 1-position ofthe 1,2,3,4-tetrahydronaphthyl ring.

m/s Example R¹ NMR M + H⁺ 53

0.88 (d, 6H), 1.58-1.76 (m, 5H), 1.93-2.08 (m, 2H), 2.24 (d, 2H),2.60-2.76 (m, 10H), 3.88 (m, 1H), 7.02-7.18 (m, 3H), 7.78 (d, 1H) 287 54(R) 1.07 (t, 3H), 1.58-1.68 (m, 2H), 1.70-1.80 (m, 259 —Et 2H),1.93-2.08 (m, 2H), 2.54-2.81 (m, 12H), 3.89 (m, 1H), 7.03-7.18 (m, 3H),7.77 (d, 1H) 55 (S) 1.07 (t, 3H), 1.58-1.68 (m, 2H), 1.71-1.80 (m, 259—Et 2H), 1.94-2.09 (m, 2H), 2.54-2.81 (m, 12H), 3.89 (m, 1H), 7.03-7.18(m, 3H), 7.77 (d, 1H) 56 (R) 0.88 (t, 3H), 1.44-1.56 (m, 2H). 1.59-1.71(m, 273 -n-Pr 2H), 1.72-1.82 (m, 2H), 1.93-2.08 (m, 2H), 2.43-2.48 (m,2H), 2.62-2.80 (m, 10H), 3.88 (m, 1H), 7.02-7.18 (m, 3H), 7.77 (d, 1H)57 (S) 0.88 (t, 3H), 1.43-1.56 (m, 2H), 1.58-1.70 (m, 273 -n-Pr 2H),1.70-1.81 (m, 2H), 1.93-2.08 (m, 2H), 2.43-2.48 (m, 2H), 2.60-2.80 (m,10H), 3.88 (m, 1H), 7.02-7.18 (m, 3H), 7.77 (d, 1H)

EXAMPLE 58

Following conventional procedures well known in the pharmaceutical artthe following representative pharmaceutical dosage forms containing acompound of formula I can be prepared:

(a) Tablet mg/tablet Compound of Formula 1 50.0 Mannitol, USP 223.75Croscarmellose sodium 60 Maize starch 15.0 Hydroxypropylmethylcellulose(HPMC), USP 2.25 Magnesium stearate 3.0 (b) Capsule mg/capsule Compoundof Formula 1 10.0 Mannitol, USP 488.5 Croscarmellose sodium 15.0Magnesium stearate 1.5

c) Injection

For intravenous administration, a compound of Formula I is dissolved inan isotonic sterile solution (5 mg/ml).

What is claimed is:
 1. A compound of the formula (I)

wherein R is hydrogen, C₁₋₁₀alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkylC₁₋₆alkyl, phenylC₁₋₆alkyl or phenyl; R¹ is C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆alkoxy, halo, hydroxy, C₁₋₆alkanoyl, haloC₁₋₆alkyl,cyano or nitro; m is 0, 1 or 2; R² is C₁₋₆alkyl; n is 0, 1 or 2; whereinany phenyl ring is optionally substituted; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1 wherein: Ris hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₆alkyl,phenylC₁₋₆alkyl or phenyl; R¹ is C₁₋₆alkyl, C₁₋₆alkoxy, halo, hydroxy,haloC₁₋₆alkyl, cyano or nitro; m is 0, 1 or 2; R² is C₁₋₆alkyl, and n is0, 1 or 2; wherein any phenyl ring is optionally substituted.
 3. Acompound according to claim 1 wherein R is hydrogen or C₁₋₆alkyl.
 4. Acompound according to claim 1 wherein R is phenylC₁₋₆alkyl.
 5. Acompound of formula (I) according to claim 1 wherein R is hydrogen,C₁₋₆alkyl or phenylC₁₋₆alkyl and R¹ is hydrogen or C₁₋₆alkoxy.
 6. Acompound according to claim 1 wherein the chiral centre at the1-position of the 1,2,3,4-tetrahydronaphthalene ring hasS-stereochemistry.
 7. A compound according to claim 1 selected from: (R)1-methyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine; (S)1-methyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine; (R)1-ethyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine; (S)1-ethyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine;1-propyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine;1-propyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine; (R)1-isopropyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine; (S)1-isopropyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine; (R)1-(2-methylpropyl)-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine;(S)1-(2-methylpropyl)-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine;1-(3-methylbutyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine;1-(3-methylbutyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine;(R) 1-(2-phenethyl)-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine;1-(2-phenethyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine; (R)1-(3-phenylpropyl-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine,and1-(3-phenylpropyl)-4-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine.8. A process for preparing a compound of the formula (I)

or a pharmaceutically acceptable salt thereof, wherein R is hydrogen,C₁₋₁₀alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₆alkyl, phenylC₁₋₆alkyl orphenyl; R¹ is C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy, halo, hydroxy,C₁₋₆alkanoyl, haloC₁₋₆alkyl, cyano or nitro; m is 0, 1 or 2; R² isC₁₋₆alkyl; n is 0, 1 or 2; wherein any phenyl ring is optionallysubstituted, which process comprises: reacting a compound of formula(III) with a compound of formula (IV):

 wherein L is a leaving group; or  deprotecting a compound of formula(V):

wherein P is a protected group R; wherein any functional group isprotected, if necessary, and: removing any protecting groups; optionallyconverting a compound of formula (I) into another compound of formula(I); optionally forming a pharmaceutically acceptable salt.
 9. Apharmaceutical composition which comprises a compound according to claim1 and a pharmaceutically acceptable carrier.
 10. A method of treating anischemia-caused neurological disorder wherein inhibition of the[³H]-emopamil binding site is beneficial which comprises administeringto a patient in need thereof an effective amount of a compound accordingto claim
 1. 11. A method of treating an ischaemia-caused neurologicaldisorder selected from stroke, head trauma and transient cerebralischemic attack which comprises administering to a patient in needthereof an effective amount of a compound according to claim 1.